Oxazinoquinazolinones

ABSTRACT

CHEMICAL COMPOUNDS OF THE FORMULA:   2-R1,3-R2,4-R3,X,Y-2,3,4,10-TETRAHYDRO-1,2-OXAZINO(3,2-B)-   QUINAZOLIN-10-ONE   WHEREIN XA AND Y EACH REPRESENT A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN OR LOWER ALKYL AND EACH R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL. THE COMPOUNDS HAVE VALUABLE ANTI-INFLAMMATORY ACTIVITY IN STANDARD LABORATORY ANIMALS.

United States Patent 3,801,574 OXAZINOQUINAZOLINONES David B. Reisner, Hightstown, Bernard J. Ludwig, North Brunswick, and Frank M. Berger, Princeton, N.J., as-

drogen and lower alkyl. As used herein the term lower alkyl" signifies alkyl radicals having from 1-6 carbon atoms. These compounds can exist and can be used in the form of the free base or an acid addition salt thereof with signors to Carter-Wallace, Inc., New York, NY. 5 f g acceptflbie and suqh as hydrochloric No Drawing. Filed June 19 1972 Ser. No. 264 312 P the Int CL C07d 87/04 The compounds of the invention can be convemently s CL 260 244 R 16 Claims prepared by reacting an appropriate alkyl anthranilate with a suitable 4-halogenoalkanoic acid halide in the presence of an acid acceptor. The resulting amide-ester is ABSTRACT OF THE DISCLOSURE then reacted with hydroxylamine hydrochloride in the Chemical compounds of the formula: presence of alkali to obtain the desired compounds. The

reactions involved are as follows:

X 0 R] x mend/Henson N/ NH: Y

i H 1 I Wherein X and Y each represent a member selected from 20 fi i R i hydrogen or lower alkyl and each Z the group consisting of hydrogen, halogen or lower alkyl c onne or and each R is selected from the group consisting of hy- X x 0 drogen and lower alkyl. The compounds have valuable NO R1 anti-inflammatory activity in standard laboratory animals. 1 yl 112N011 T NHCOOHCHCHZ; R, The present 1nvent1on relates to novel chemlcal com- Y l l I Y N H pounds. More particularly, the invention relates to novel H fg g fggi g yg figg ss pharmacologlcany useful The ester of the substituted anthranilic acid is prepared by The oxazinoquinazolinone compounds of the present (I) F P the and alcohol m the Presence of invention have the following general chemical structure: sulfuric i hydrcl.11nc.acld or (2) rfaactmg the appropnate 1sato1c anhydride with an alcohol 1n the presence x 0 of a strong base. The 4-halogenoalkanoic acid halide is /0 prepared by the reaction of a 4-halogenoalkanoic acid N with thionyl chloride or a phosphorus halide or by the reaction of an appropriately substituted 'y-butyrolactone X/\N/ H with thionyl chloride in the presence of zinc chloride. Y Table 1 and the examples which follow set forth the H 40 physical constants of a representative number of the novel wherein X and Y each represent a member selected from compounds and the examples which follow illustrate meththe group consisting of hydrogen, halogen or lower alkyl ods of preparation respectively. These are in no event to and each R is selected from the group consisting of hybe construed as limiting.

TABLE 1 R2 H N Y Carbon Hydrogen Nitrogen Other elements Cpd. X and Recryst. M.P., No. R1 R2 R solvent 0. Formula Calcd. Found Calcd. Found Calcd. Found Calcd. Found H H H EtOAc 161-162 CnHmNzOz 65.33 55.14 4.98 5.03 13.86 13 77 1 15 83 16.05 H H H EtOH CnHoClNzOa 55.83 56.01 3.83 3.75 11.84 0 H C12H12Nz0z 66.65 66.47 5.59 5.48 H H C12H12N2O2 66.65 66.80 5.59 5.52 H C12H12N20a 66. 65 66. 42 5. 59 5. 45 H C12H12Nz0z 66. 66. 40 5. 59 5. 52 H H H Trlchlor 212 CuHgGhNzOz 48.73 48.73 2.97 2.95

2 Chlorine. 3 Decomposition.

EXAMPLE 1 A solution of 129 g. (0.85 mole) of methyl anthranilate in 350 ml. of pyridine was cooled to C., and 120 g. (0.85 mole) of 4-chlorobutyryl chloride was added dropwise to the stirred solution. The reaction mixture was stirred at room temperature overnight. The pyridine was removed by distillation under reduced pressure, water was added and the mixture was extracted with chloroform. The chloroform soluion was dried over Drierite and evaporated to dryness to yield 216 g. of an oil. The oil was treated with petroleum ether and allowed to crystallize. The crude product was separated by filtration and used in the following reaction without further purification.

To a stirred solution of 102 g. (2.6 moles) of sodium hydroxide and 119 g. (1.7 moles) of hydroxylamine hydrochloride in 300 ml. of water cooled at 0 C., was added a solution of the above crude intermediate dissolved in 150 ml. of ethanol. The rate of addition was adjusted to maintain a reaction temperature of 0 to 20 C. The resulting solution was stirred at room temperature overnight. The alcohol was removed by distillation and the mixture was extracted with 400 ml. of chloroform. The chloroform solution was washed with water, dried over Drierite and concentrated to dryness. The oil (100 g.) which crystallized on standing was washed with ether and recrystallized from ethyl acetate giving 59.9 g. of 3,4- dihydro-(1,2)-oxazino[3,2-b]quinazolin-10(2H)-one.

EXAMPLE 2 Preparation of 2-methyl-3,4-dihydro-(1,2)-oxazino- [3,2-b]quinazolin-10(2H)-one A mixture of 100 g. of y-valerolactone, 100 ml. of thionyl chloride and 0.5 g. of zinc chloride was heated on a steam bath overnight and then distilled at 83-85 C. and approximately 20 mm. giving 60.9 g. of 4-chlorovaleryl chloride. The acid chloride was allowed to react with methyl anthranilate, and the resulting intermediate was treated with hydroxylamine as described in Example 1.

EXAMPLE 3 Preparation of 4-methyl-3,4-dihydro-( 1,2 -oxazino- [3,2-b] quinazolin-10(2H) -one 4-chloro-2-methylbutyryl chloride (B.P. 7578 C. at approximately 15 mm.) prepared from 2-methyl- -butyrolactone according to the method detailed in Example 2 was allowed to react with methyl anthranilate and hydroxylamine according to the method described in Example 1.

EXAMPLE 4 Preparation of 3-methyl-3,4-dihydro-(1,2)-oxazino- [3,2-b]quinazolin-10(2H)-one by hydroxylamine according to the method given in Example 1.

EXAMPLE Preparation of 8-chloro-3,4-dihydro-( 1,2 -oxazino- [3,2-b]quinazolin-10(2H)-one Methyl S-chloro-Z-(4-chlorobutyramido) benzoate 107 gm), obtained from 71 g. of methyl S-chloroanthranilate and 54 g. of 4-chlorobutyryl chloride, was treated with 51.5 g. of hydroxylamine hydrochloride and 44.4 g. of

sodium hydroxide. The crude product, an oil, was dis solved in ethanol and dry hydrogen chloride was added. The solid hydrochloride was removed by filtration and was converted to the free base with aqueous sodium hydroxide. The base was extracted into chloroform and the organic solution was dried and concentrated to dryness giving 35.2 g. of a solid which was recrystallized from ethanol.

EXAMPLE 6 Preparation of 8-methyl-3 ,4-dihydro- 1,2)-oxazino- [3,2-b] quinazolin-10(2H) -one 38 g. of Compound 4 in Table 1 was obtained from 86.3 g. of methyl S-methylanthranilate, 75 g. of 4-chlorobutyryl chloride and 65.5 g. of hydroxylamine hydrochloride according to the procedure given in Example 5.

EXAMPLE 7 Preparation of 6,8-dichloro-3,4-dihydro-(1,2)-oxazino [3,2-b] quinazolin- 10 (2H) -one 7 4.6 g. of Compound 7 in Table 1 was obtained from 30.5 g. of methyl 3,S-dichloroanthranilate, 19.7 g. of 4-chlorobutyryl chloride and 19.2 g. of hydroxylamine hydrochloride according to the procedure detailed in Example 1.

EXAMPLE 8 Preparation of 3,4-dihydro-(1,2)-oxazino[3,2-b] quinazolin-10(2H)-one hydrochloride A sample of the base, 3,4-dihydro-(1,2)-oxazino[3,2- b]quinazolin-10(2H)-one, was added to a heated solution of hydrogen chloride in ethanol. The resulting mixture was allowed to cool to room temperature and filtered to remove the desired hydrochloride of 3,4-dihydro-(1,2)- oxazino[3,2-b]quinazolin-10(2H)-one. The salt melted with decomposition at 273 C.

Analysis.Ca1cd. for C H ClN O (percent): C, 55.36; H, 4.65; Cl, 14.85; N, 11.74. Found (percent): C, 55.39; H, 4.72; Cl, 14.70; N, 11.85.

The compounds of the present invention are useful as a result of their valuable pharmacological properties, for example, they are valuable anti-inflammatory agents, as evidenced by their ability to inhibit the local edema formation characteristic of inflammatory states when administered systemically to warm-blooded animals.

The procedure described below (Winters et al., Proc. Soc., Exp. Biol. Med., 111, 544, 1962) was used to establish the effectiveness of these compounds in the hind paw edema induced by carrageenin in the rat. This procedure is considered suitable for demonstrating anti-inflammatory activity of drug compounds in laboratory animals.

Male rats of the Sprague-Dawley strain (Charles River Laboratories) weighing :20 grams were used for this study. Six animals were used for each drug dose. The drug was suspended in 1 percent aqueous solution of gum acacia, and each rat received 10 mL/kg. of the appropriate concentration of drug suspension by oral intubation; controls were given a similar volume of the vehicle. One hour later, edema in the right hind paw was induced by the subplantar injection of 0.05 ml. of 1 percent calcium carrageenin dissolved in 0.15 N sodium chloride. The volume of the foot was determined immediately and again 3 hours later. The diti'erence was recorded as edema volume. Foot volume was measured by immersion of the foot in water at the level of the lateral malleolus, and determining the volume of water displaced by the foot. The ED may be defined as the dose in which edema formation is inhibited by 25 percent or more in 50 percent of the rats when compared to the mean value of the controls.

When tested by the method set forth above, the Compound No. 1 of Table 1, 3,4-dihydro-(1,2)-oxazino[3,2-b] quinazolin-10(2H)-one was found to have an ED value of 40:23 mg./ kg. of animal weight.

The pharmaceutical compositions of the present invention are prepared by incorporating the active ingredient with a suitable pharmaceutical carrier. The carrier must be of such nature that the novel compositions may be administered systemically to warm-blooded animals. The term systemically as used herein, means a mode of administration whereby the active ingredient, when given to warm-blooded animals, is effective in the whole body and not merely at the locus of application. This included parenteral and other methods of administration.

The active ingredients of the present invention are preferably administered orally in the form of tablets or capsules. Suitable solid pharmaceutical carriers which can be utilized include, for example, starch, lactose, sucrose, glucose, gelatin, and the like. When the composition is in the form of a solid, the active ingredient is generally in the amount of from about 25 to about 95 percent by weight of the total composition.

The active ingredients of the invention can also be dissolved in a liquid pharmaceutical carrier, such as, for example, propylene glycol, polyethylene glycol, water, saline, and mixtures thereof, to form a solution suitable for injection. Such injectable solutions generally contain from about 0.05 gram to about 30 grams of active ingredient per 100 ml. of solution.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula:

N' RI R: N Y H and the physiologically acceptable acid addition salts thereof wherein X and Y are each a member selected from the group consisting of hydrogen, halogen or lower alkyl and each R is selected from the group consisting of hydrogen and lower alkyl.

2. A compound of claim 1 wherein X, Y, R R and R are each hydrogen.

3. A compound of claim 1 wherein X is halogen and Y, R R and R are hydrogen.

4. A compound of claim 1 wherein R is lower alkyl and X, Y, R R and R are hydrogen.

5. A compound of claim 1 wherein X is lower alkyl and Y, R R and R are hydrogen.

6. A compound of claim 1 wherein R is lower alkyl and X, Y, R and R are hydrogen.

7,. A compound of claim 1 wherein R is lower alkyl and X, Y, R and R are hydrogen.

8. A compound of claim 1 wherein X and Y are halogen and R R and R are hydrogen.

9. Z-methyl 3,4 dihydro-(l,2)-oxazino[3,2-b1quinazolin-l0(2H)-one.

10. 4 methy1-3,4-dihydro-(1,2)-oxazino[3,2-b]-quinazolin-l0(2H)-one.

11. 3,4-dihydro (1,2) oxazino[3,2-b]quinazolin-10 (2H)-one.

12. 3-methyl 3,4 dihydro-(1,2)-oxazino[3,2-b]quinazolin-l0(2H)-one.

13. 8-chloro-3,4-dihydro (1,2) oxazino[3,2-b]quinazolin-10(2H)-one.

14. 8-methyl-3,4-dihydro (1,2) oXazino[3,2-b]quinazolin-10(2H)-one.

15. 6,8-dichloro-3,4-dihydro (1,2) oxazino[3,2-b] quinazolin-l0(2H)-one.

16. 3,4-dihydro (1,2) oxazino[3,2-b]quinazolin-IO (2H)-one hydrochloride.

References Cited UNITED STATES PATENTS 3,684,805 8/1972 Reisner et a1. 260-244 HARRY I. MOATZ, Primary Examiner US. Cl. X.R. 

